• Molecules and Cells
• /
• v.41 no.7
• /
• pp.695-702
• /
• 2018

The inner ear is a complex sensory organ responsible for hearing and balance. Formation of the inner ear is dependent on tight regulation of spatial and temporal expression of genes that direct a series of developmental processes. Recently, epigenetic regulation has emerged as a crucial regulator of the development of various organs. However, what roles higher-order chromatin organization and its regulator molecules play in inner ear development are unclear. CCCTC-binding factor (CTCF) is a highly conserved 11-zinc finger protein that regulates the three-dimensional architecture of chromatin, and is involved in various gene regulation processes. To delineate the role of CTCF in inner ear development, the present study investigated inner ear-specific Ctcf knockout mouse embryos (Pax2-Cre; $Ctcf^{fl/fl}$). The loss of Ctcf resulted in multiple defects of inner ear development and severely compromised otic neurogenesis, which was partly due to a loss of Neurog1 expression. Furthermore, reduced Neurog1 gene expression by CTCF knockdown was found to be associated with changes in histone modification at the gene's promoter, as well as its upstream enhancer. The results of the present study demonstrate that CTCF plays an essential role in otic neurogenesis by modulating histone modification in the Neurog1 locus.

• Journal of Applied Biological Chemistry
• /
• v.57 no.4
• /
• pp.379-386
• /
• 2014

Chromatin is an instructive DNA structure that can widely respond to external signals. An important change of chromatin is the modifications of histone for this regulation. There are accumulating lists of these modifications and the complexity of their action is gradually understood. It is evident that histone modifications play important roles in most biological processes that are involved in the expression or repression of DNA. The surface of nucleosomes is susceptible to multiplicity of modifications. Chromatin modifications can play either by eliminating chromatin contacts or by recruiting non-histone proteins to chromatin. Many of these regulations seem to be epigenetically inherited. Thus, histone modifications are closely correlated with many fundamental biological processes in animal, plant and microbial kingdoms. Failures of histone modification lead, in general, to defective chromosome condensation or decondensation, impeding many biological functions including development, maturation, and protection against various diseases.

• Journal of Environmental Health Sciences
• /
• v.35 no.5
• /
• pp.343-354
• /
• 2009

Since Barker found associations between low birth weight and several chronic diseases later in life, the hypothesis of fetal origins of adult disease (aka, Barker Hypothesis) and epigenetics have been emerging as a new paradigm for geneenvironment interaction of chronic disease. Epigenetics is the study of heritable changes in gene silencing that occur without any change in DNA sequence. Gene expression can be regulated by several epigenetic mechanisms, including DNA methylation and histone modifications, which may be associated with chronic conditions, such as cancers, cardiovascular disease, and type-2 diabetes. One carbon metabolism which involves the transfer of a methyl group catalyzed by DNA methyltransferase is an important mechanism by which DNA methylation occurs in promoter regions and/or repetitive elements of the genome. Environmental factors may induce epigenetic modification through production of reactive oxygen species, alteration of methyltransferase activity, and/or interference with methyl donors. In this review, we introduce recent studies of epigenetic modification and environmental factors, such as heavy metals, environmental hormones, air pollution, diet and psychosocial stress. We also discuss epigenetic perspectives of early life environmental exposure and late life disease occurrence.

• Development and Reproduction
• /
• v.15 no.4
• /
• pp.273-279
• /
• 2011

Epigenetic regulation is a phenomenon that changes the gene function without changing the underlying DNA sequences. Epigenetic status of chromosome is regulated by mechanisms such as histone modification, DNA modification, and RNAi silencing. In this review, we focused on histone methylation for epigenetic regulation in ES cells. Two antagonizing multiprotein complexes regulate methylation of histones to guide expression of genes in ES cells. The Polycomb repressive complex 2 (PRC2), including EED, EZH2, and SUZ12 as core factors, contributes to gene repression by increasing trimethylation of H3K27 (H3K27me3). In contrast, the Trithorax group (TrxG) complex including MLL is related to gene activation by making H3K4me3. PRC2 and TrxG accompany a variety of accessory proteins. Most prominent feature of epigenetic regulation in ES cells is a bivalent state in which H3K27me3 and H3K4me3 appear simultaneously. Concerted regulation of PRC2, TrxG complex, and H3K4- or H3K27-specific demethylases activate expression of pluripotency-related genes and suppress development-related genes in ES cells. Modified balance of the regulators also enables ES cells to efficiently differentiate to a variety of cells upon differentiating signals. More detailed insights on the epigenetic regulators and their action will lead us to better understanding and use of ES cells for future application.

• BMB Reports
• /
• v.55 no.3
• /
• pp.111-112
• /
• 2022

We visualized the distribution of heterochromatin in a single nucleus using plasmonic nanoparticle-conjugated H3K9me3 and H3K27me3 antibodies. Due to distance-dependent plasmonic coupling effects between nanoprobes, their scattering spectra shift to longer wavelengths as the distance between heterochromatin histone markers reduced during oncogene-induced senescence (OIS). These observations were supported by simulating scattering profiles based on considerations of particle numbers, interparticle distances, and the spatial arrangements of plasmonic nanoprobes. Using this plasmon-based colourimetric imaging, we estimated changes in distances between H3K9me3 and H3K27me3 during the formation of senescence-associated heterochromatin foci in OIS cells. We anticipate that the devised analytical technique combined with high-spatial imaging and spectral simulation will eventually lead to a new means of diagnosing and monitoring disease progression and cellular senescence.

• Animal cells and systems
• /
• v.12 no.3
• /
• pp.117-125
• /
• 2008

One of the interesting trends in genome research is the study about epigenetic modification above single gene level. Epigenetics refers study about heritable change in the genome, which accompany modification in DNA or Chromatin besides DNA sequence alteration. We used to have the idea that the coding potential of the genome lies within the arrangement of the four bases A, T, G, C; However, additional information that affects phenotype is stored in the distribution of the modified base 5-methylcytosine. This form of information storage is flexible enough to be adapted for different somatic cell types, yet is stable enough to be retained during mitosis and/or meiosis. Epigenetic modification is a modification of the genome, as opposed to being part of the genome, so is known as "epigenetics"(Greek for "upon" genetics). This modification could be methylation on Cytosine base or post translational modification on histone protein(methylation, acetylation, phosphorylation, Sumoylation)($Dimitrijevi\hat{E}$ et al 2005). In this review, we would like to focus on the relationship of DNA methylation and cancer.

• BMB Reports
• /
• v.48 no.3
• /
• pp.131-138
• /
• 2015

Cardiac hypertrophy is a form of global remodeling, although the initial step seems to be an adaptation to increased hemodynamic demands. The characteristics of cardiac hypertrophy include the functional reactivation of the arrested fetal gene program, where histone deacetylases (HDACs) are closely linked in the development of the process. To date, mammalian HDACs are divided into four classes: I, II, III, and IV. By structural similarities, class II HDACs are then subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular function and regulation of class IIa HDACs depend largely on the phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take place primarily in the nucleus. In response to stresses, posttranslational modification (PTM) processes, dynamic modifications after the translation of proteins, are involved in the regulation of the activities of those hypertrophy-related HDACs. In this article, we briefly review 1) the activation of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and its implications in the regulation of HDAC2 activity.

• Biomolecules & Therapeutics
• /
• v.29 no.2
• /
• pp.184-194
• /
• 2021

Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.

• Biomedical Science Letters
• /
• v.28 no.2
• /
• pp.109-119
• /
• 2022

Histone proteins can be modified by the addition of acetyl group or methyl group to specific amino acids. The modifications have different distribution patterns in chromatin. Recently, histone modifications are studied based on ChIP-seq data, which requires reasonable analysis of sequencing data depending on their distribution patterns. Here we have analyzed histone H3K27ac and H3K27me3 ChIP-seq data and it showed that the H3K27ac is enriched at narrow regions while H3K27me3 distributes broadly. To properly analyze the ChIP-seq data, we called peaks for H3K27ac and H3K27me3 using MACS2 (narrow option and broad option) and SICER methods, and compared propriety of the peaks using signal-to-background ratio. As results, H3K27ac-enriched regions were well identified by both methods while H3K27me3 peaks were properly identified by SICER, which indicates that peak calling method is more critical for histone modifications distributed broadly. When ChIP-seq data were compared in different sequencing depth (15, 30, 60, 120 M), high sequencing depth caused high false-positive rate in H3K27ac peak calling, but it reflected more properly the broad distribution pattern of H3K27me3. These results suggest that sequencing depth affects peak calling from ChIP-seq data and high sequencing depth is required for H3K27me3. Taken together, peak calling tool and sequencing depth should be chosen depending on the distribution pattern of histone modification in ChIP-seq analysis.

• Journal of Ginseng Research
• /
• v.48 no.3
• /
• pp.298-309
• /
• 2024

Background: 20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown. Methods: Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance. Results: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3. Conclusions: This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.